{"gene":"OPCML","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2003,"finding":"OPCML (OBCAM) is a GPI-anchored IgLON family cell adhesion molecule that is somatically inactivated in epithelial ovarian cancer by allele loss and CpG island methylation; a somatic missense mutation showed loss of function, and restored expression suppressed tumor growth in vitro and in vivo, establishing tumor suppressor function.","method":"Loss of heterozygosity analysis, methylation-specific PCR, ectopic expression with in vitro and in vivo tumor growth assays, somatic missense mutation functional analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (LOH, methylation, functional rescue in vitro and in vivo, mutation analysis) in a single rigorous study, widely replicated across subsequent labs","pmids":["12819783"],"is_preprint":false},{"year":2003,"finding":"OBCAM (OPCML) is localized postsynaptically at dendritic and somatic synapses in adult cerebral cortex and hippocampus, and interacts both heterophilically and homophilically with the related IgLON family member Kilon, as demonstrated by cross-linker binding analysis and immunoprecipitation.","method":"Electron microscopy, immunohistochemistry, cross-linker binding analysis, immunoprecipitation","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by EM and reciprocal IP for interaction, single lab but two orthogonal methods","pmids":["12617969"],"is_preprint":false},{"year":2012,"finding":"OPCML functions as a cell-surface repressor-adaptor that negatively regulates a specific repertoire of receptor tyrosine kinases (EPHA2, FGFR1, FGFR3, HER2, HER4) in ovarian cancer by binding their extracellular domains, redirecting trafficking via non-clathrin/caveolin-1-associated endocytosis, and promoting polyubiquitination-dependent proteasomal degradation. Recombinant OPCML domains 1–3 recapitulate this mechanism in vitro and in vivo.","method":"Co-immunoprecipitation, trafficking assays (clathrin vs. non-clathrin endocytosis), ubiquitination assays, proteasome inhibitor experiments, in vitro and in vivo (murine intraperitoneal) tumor growth assays with recombinant protein","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, trafficking, ubiquitination, proteasome inhibition, in vivo rescue) in a single rigorous study establishing the mechanistic pathway","pmids":["22585860"],"is_preprint":false},{"year":2007,"finding":"OBCAM (OPCML) is localized at postsynaptic spines in hippocampal neurons; inhibition of OBCAM function with specific antibody significantly decreased synapse number on dendrites, antisense knockdown impaired synapse formation, and overexpression augmented synapse formation, establishing a role in synaptogenesis. Activity-dependent internalization of OBCAM occurs via a lipid raft/cholesterol-dependent (filipin-sensitive) pathway.","method":"Immunofluorescence microscopy, antibody function-blocking, antisense oligodeoxynucleotide knockdown, plasmid overexpression, 4-aminopyridine neuronal activity stimulation, filipin treatment internalization assay","journal":"Brain research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal loss-of-function and gain-of-function approaches with quantitative phenotypic readout, single lab but rigorous","pmids":["17658490"],"is_preprint":false},{"year":2005,"finding":"Oncogenic RAS (HRASV12) directly mediates epigenetic silencing of OPCML by promoting CpG island promoter hypermethylation; siRNA knockdown of HRASV12 reversed OPCML promoter methylation and restored expression, demonstrating that elevated RAS signaling drives OPCML epigenetic inactivation.","method":"Methylation-sensitive PCR, 5-aza-2'-deoxycytidine demethylation, stable siRNA knockdown of HRASV12, RT-PCR for OPCML re-expression","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (siRNA rescue) plus pharmacological demethylation and methylation-sensitive PCR; single lab but multiple orthogonal approaches clearly establishing causal direction","pmids":["16384911"],"is_preprint":false},{"year":2018,"finding":"OPCML directly interacts with the activated RTK AXL (preferentially when AXL is bound by its ligand Gas6), causing AXL to accumulate in cholesterol-rich lipid domains where OPCML resides. There, OPCML brings phospho-AXL into proximity with the lipid domain-restricted phosphatase PTPRG, which dephosphorylates AXL, preventing AXL-mediated transactivation of cMET and EGFR, inhibiting sustained phospho-ERK signaling, Slug induction, EMT, cell migration, and invasion.","method":"Co-immunoprecipitation, lipid domain fractionation, phosphatase (PTPRG) proximity/activity assays, ERK signaling assays, migration/invasion assays, in vivo AXL inhibitor (R428) combination experiments","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, lipid domain fractionation, multiple downstream signaling readouts, in vivo validation; multiple orthogonal methods in a single study","pmids":["29907679"],"is_preprint":false},{"year":2019,"finding":"X-ray crystal structure of OPCML solved to 2.65 Å resolution reveals an extended arrangement of three immunoglobulin-like domains and homodimerization via contacts between membrane-distal domains. Somatic missense mutations from tumor databases were shown to impair anchorage-independent growth, interaction with activated RTKs, migration, invasion in vitro, and tumor growth in vivo.","method":"X-ray crystallography, structure-guided mutagenesis of clinical missense variants, anchorage-independent growth assays, Co-IP with RTKs, migration/invasion assays, in vivo tumor growth assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and multiple in vitro/in vivo assays in a single rigorous study","pmids":["31316070"],"is_preprint":false},{"year":2019,"finding":"OPCML interacts with EphB2 in hippocampal neurons and controls spine stability by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml ablation in mice reduces phosphorylated cofilin levels and dysregulates F-actin dynamics, disturbing spine maturation; aripiprazole partially restores behavior and phospho-cofilin levels.","method":"Co-immunoprecipitation (OPCML-EphB2 interaction), Opcml knockout mouse model, phospho-cofilin immunoblotting, F-actin dynamics assays, spine morphology analysis, behavioral testing (cognitive, sensorimotor gating), pharmacological rescue with aripiprazole","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing direct interaction, genetic knockout with defined molecular phenotype (phospho-cofilin, F-actin), pharmacological rescue; multiple orthogonal methods","pmids":["31577955"],"is_preprint":false},{"year":2017,"finding":"OPCML interacts with HER2 but not EGFR; this interaction disrupts HER2-EGFR heterodimer formation and sensitizes HER2-expressing ovarian and breast cancer cells to the EGFR/HER2 inhibitors lapatinib and erlotinib, demonstrating that OPCML-HER2 binding indirectly suppresses EGFR signaling through heterodimer disruption.","method":"Co-immunoprecipitation (OPCML-HER2 interaction), HER2-EGFR heterodimerization assay, cell viability assays with lapatinib/erlotinib, in vitro and clinical correlation","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional drug sensitization assays, single lab, two orthogonal in vitro methods","pmids":["28775148"],"is_preprint":false},{"year":2015,"finding":"Restored OPCML expression in colorectal cancer cells inhibits TGFβ-Smad signaling, reverses a partial epithelial-to-mesenchymal transition (EMT), and inhibits cell migration and invasion; OPCML expression was also found to be associated with the nuclear receptors ERRα and RORα.","method":"Ectopic OPCML expression, Smad phosphorylation western blotting, EMT marker analysis, migration/invasion assays, nuclear receptor association assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ectopic expression with defined signaling readouts (Smad phosphorylation, EMT markers), single lab with multiple assays","pmids":["26175934"],"is_preprint":false},{"year":1996,"finding":"OBCAM (OPCML) is linked to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, demonstrated by release from the membrane upon treatment with phosphatidylinositol-specific phospholipase C (PI-PLC) in transfected cells and in bovine brain membranes.","method":"PI-PLC treatment of transfected Cos1 cells and bovine brain P2 membranes, immunoblotting, N-glycanase digestion showing N-glycosylation","journal":"Brain research. Molecular brain research / Neurochemistry international","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic cleavage (PI-PLC) demonstrating GPI anchor, replicated in both transfected cells and native brain membranes in independent studies","pmids":["8965653","8740443"],"is_preprint":false},{"year":1996,"finding":"GP55 (a chick homolog closely related to OBCAM/OPCML) inhibits neurite outgrowth from dorsal root ganglion neurons when presented as a substrate, and an antiserum against it reverses this inhibition, establishing that the IgLON family members can function as inhibitors of neurite outgrowth.","method":"Substrate-bound neurite outgrowth inhibition assay, antibody reversal assay, peptide sequencing, PCR cloning with homology to OBCAM","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro functional assay with antibody reversal control; this is a chick ortholog study with functional relevance to the mammalian protein","pmids":["9004047"],"is_preprint":false},{"year":2009,"finding":"OBCAM (OPCML) in astrocytes is expressed prominently at filopodia and cellular processes and controls astrocyte proliferation and cell size; antibody-induced clustering of OBCAM (but not Fab fragment treatment) promoted astrocyte proliferation, and OBCAM overexpression increased astrocyte cell size. OBCAM expression is upregulated on reactive astrocytes after brain injury in vivo.","method":"Confocal microscopy, anti-OBCAM IgG vs. Fab fragment treatment, OBCAM overexpression, Ki-67 proliferation marker, in vivo brain injury model","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Fab vs. whole IgG comparison provides mechanistic insight into clustering requirement; overexpression phenotype; single lab with multiple methods","pmids":["19943852"],"is_preprint":false},{"year":2003,"finding":"OBCAM (OPCML) is efficiently targeted to the dendritic surface of polarized cortical and hippocampal neurons, resides in lipid rafts (resistant to Triton X-100 extraction at 4°C and released by PI-PLC), and shows surface localization preferentially on dendrites compared to somata.","method":"Live-cell immunofluorescence (pre-fixation antibody labeling), PI-PLC treatment, detergent fractionation (Triton X-100 raft isolation), double labeling with synapsin I and MAP2","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell surface labeling with biochemical fractionation confirming raft localization; single lab, two orthogonal methods","pmids":["12850579"],"is_preprint":false},{"year":2021,"finding":"Ectopic OPCML expression in cholangiocarcinoma cells inhibits proliferation by inducing apoptosis via inactivation of AXL/STAT3 signaling, and suppresses migration and invasion by downregulating Rho GTPases (RHOA, RAC1, CDC42).","method":"Ectopic OPCML expression (pcDNA3.1 vector), AXL/STAT3 phosphorylation western blotting, Rho GTPase activity assays, proliferation, migration, and invasion assays","journal":"Cancer genomics & proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ectopic expression with defined signaling readouts and Rho GTPase measurements; single lab, multiple pathways examined","pmids":["34697068"],"is_preprint":false},{"year":2022,"finding":"GPBAR1 activation increases OPCML expression in dopaminergic neurons by promoting nuclear localization of the cohesin subunit RAD21, which in turn upregulates Opcml transcription, thereby protecting neurites and synapses in a Parkinson's disease model. This establishes RAD21 as a transcriptional regulator upstream of OPCML.","method":"DA neuron-specific Gpbar1 knockdown in mice, central GPBAR1 activation with INT-777, RAD21 nuclear fractionation/localization, OPCML expression measurement, neurite/synapse morphometry, behavioral assays","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic knockdown and pharmacological activation with mechanistic fractionation data, single lab","pmids":["36152741"],"is_preprint":false},{"year":2024,"finding":"Opcml deficiency in mice leads to decreased neuronal excitability and impaired glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons, specifically via postsynaptic AMPA/NMDA receptor dysfunction, resulting in disturbed excitatory/inhibitory balance. Aripiprazole rescued impaired glutamatergic transmission alongside behavioral improvement.","method":"Whole-cell patch clamp recordings in Opcml knockout mice, AMPAR/NMDAR current analysis, E/I balance measurements, pharmacological rescue with aripiprazole","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct electrophysiology in genetic knockout model with pharmacological rescue, single lab","pmids":["39420375"],"is_preprint":false},{"year":2006,"finding":"Lentiviral expression of OPCML in ovarian cancer cell line A2780 increased cell-surface adhesion in all tested cell lines, arrested A2780 cells in G0/G1, reduced proliferation, and markedly suppressed tumorigenicity in nude mice, while having no effect on the OCC1 or normal CD1 mouse ovarian surface epithelial cells.","method":"Lentiviral OPCML transduction, cell aggregation assay, flow cytometry cell cycle analysis, CCK-8/proliferation assay, nude mouse xenograft tumorigenicity assay","journal":"Zhonghua fu chan ke za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional assays with near-100% infection efficiency; single lab, multiple assays","pmids":["16762191"],"is_preprint":false},{"year":2025,"finding":"OBCAM (OPCML) directly interacts with the extracellular N-terminal domain (NTD) of AMPA-type glutamate receptors (AMPARs), as identified by surface-restricted APEX2 proximity labeling during chemical LTP induction in cultured neurons; OBCAM was among four IgLON family members enriched in the AMPAR extracellular interactome after cLTP.","method":"Surface-restricted APEX2 proximity labeling, BioSITe-based proteomics, direct binding assay between OBCAM and AMPAR NTD","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — surface-restricted proximity labeling and direct NTD interaction assay; preprint, single lab, two orthogonal methods","pmids":["bio_10.1101_2025.07.11.664166"],"is_preprint":true}],"current_model":"OPCML (OBCAM) is a GPI-anchored, lipid raft-resident IgLON family cell adhesion molecule that functions as a broad tumor suppressor by binding the extracellular domains of specific receptor tyrosine kinases (including EPHA2, FGFR1, FGFR3, HER2, HER4, and AXL), redirecting them to non-clathrin/caveolin-1 endosomal pathways for polyubiquitination and proteasomal degradation, and cooperating with the phosphatase PTPRG to dephosphorylate and inactivate AXL; in neurons, it localizes postsynaptically at dendritic spines, interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation, and directly binds AMPA receptor extracellular domains to modulate synaptic plasticity, while its expression is epigenetically silenced in diverse cancers through RAS-driven CpG island promoter hypermethylation."},"narrative":{"mechanistic_narrative":"OPCML (OBCAM) is a GPI-anchored, lipid raft-resident IgLON family cell-surface adhesion molecule that acts as a broad tumor suppressor and a regulator of synaptic structure [PMID:12819783, PMID:8965653, PMID:8740443, PMID:22585860]. Its three-immunoglobulin-like-domain ectodomain adopts an extended arrangement and homodimerizes through membrane-distal contacts; clinical missense variants mapped onto this structure impair RTK binding, anchorage-independent growth, migration, invasion, and tumor growth [PMID:31316070]. As a cell-surface repressor-adaptor, OPCML binds the extracellular domains of a defined repertoire of receptor tyrosine kinases (EPHA2, FGFR1, FGFR3, HER2, HER4), redirecting them through non-clathrin/caveolin-1 endocytosis toward polyubiquitination-dependent proteasomal degradation [PMID:22585860]. It additionally captures ligand-activated AXL into cholesterol-rich domains where it juxtaposes phospho-AXL with the lipid-domain phosphatase PTPRG, driving AXL dephosphorylation and blocking downstream ERK signaling, EMT, migration, and invasion [PMID:29907679], and its binding to HER2 disrupts HER2-EGFR heterodimers to suppress EGFR signaling [PMID:28775148]. OPCML expression is epigenetically silenced in cancer by oncogenic RAS-driven CpG island promoter hypermethylation [PMID:12819783, PMID:16384911]. In the nervous system, OPCML localizes to postsynaptic dendritic spines within lipid rafts and undergoes activity-dependent, cholesterol-dependent internalization to promote synaptogenesis [PMID:17658490, PMID:12850579]; it interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation [PMID:31577955] and shapes glutamatergic transmission through postsynaptic AMPA/NMDA receptor function [PMID:39420375].","teleology":[{"year":1996,"claim":"Establishing how OPCML attaches to the cell surface defined it as a GPI-anchored, glycosylated membrane protein rather than a transmembrane receptor, framing all later interpretations of its raft residence and adaptor function.","evidence":"PI-PLC release and N-glycanase digestion in transfected cells and native bovine brain membranes","pmids":["8965653","8740443"],"confidence":"High","gaps":["Does not address signaling output or binding partners","No structural detail of the ectodomain"]},{"year":1996,"claim":"A closely related IgLON ortholog (GP55) was shown to inhibit neurite outgrowth and to be reversible by antibody, providing the first functional readout that IgLON family members act as cell-surface modulators of neuronal growth.","evidence":"Substrate-bound neurite outgrowth inhibition with antibody reversal in DRG neurons (chick ortholog)","pmids":["9004047"],"confidence":"Medium","gaps":["Chick ortholog, not direct OPCML evidence","Molecular partner mediating inhibition not identified"]},{"year":2003,"claim":"OPCML was established as a tumor suppressor in epithelial ovarian cancer, answering whether its frequent loss is causal by combining allele loss, methylation, a loss-of-function mutation, and functional rescue.","evidence":"LOH, methylation-specific PCR, somatic mutation analysis, and ectopic expression with in vitro and in vivo tumor growth assays","pmids":["12819783"],"confidence":"High","gaps":["Molecular mechanism of suppression unresolved at this stage","Binding partners not yet identified"]},{"year":2003,"claim":"Parallel neuronal work showed OPCML resides postsynaptically in dendritic lipid rafts and engages other IgLONs, indicating a synaptic adhesion role distinct from its tumor context.","evidence":"EM/immunohistochemistry, cross-linker binding and IP with Kilon, live-cell surface labeling and detergent raft fractionation","pmids":["12617969","12850579"],"confidence":"Medium","gaps":["Functional consequence of synaptic localization not yet tested","Homophilic vs heterophilic binding stoichiometry unresolved"]},{"year":2006,"claim":"Lentiviral restoration of OPCML demonstrated cell-cycle arrest, increased surface adhesion, and suppressed tumorigenicity, refining the tumor-suppressor phenotype to specific cellular outputs.","evidence":"Lentiviral transduction, aggregation assay, flow cytometry, proliferation and xenograft assays in ovarian cancer cells","pmids":["16762191"],"confidence":"Medium","gaps":["Mechanism linking adhesion to cell-cycle arrest not defined","Effect restricted to a subset of lines"]},{"year":2006,"claim":"The cause of OPCML silencing was traced to oncogenic RAS, showing that elevated RAS signaling drives CpG island promoter hypermethylation and that this is reversible.","evidence":"Methylation-sensitive PCR, 5-aza demethylation, and HRASV12 siRNA rescue restoring expression","pmids":["16384911"],"confidence":"High","gaps":["Intermediate methyltransferase machinery not identified","Whether other oncogenes converge on the same promoter unknown"]},{"year":2007,"claim":"Loss- and gain-of-function in hippocampal neurons established OPCML as a positive regulator of synaptogenesis and revealed activity-dependent, cholesterol-dependent internalization, linking its raft residence to a dynamic trafficking cycle.","evidence":"Antibody blocking, antisense knockdown, overexpression, activity stimulation, and filipin internalization assay","pmids":["17658490"],"confidence":"High","gaps":["Downstream effectors of synaptogenesis not defined here","Receptor partner mediating the effect unknown at this stage"]},{"year":2009,"claim":"OPCML was shown to control astrocyte proliferation and size in a clustering-dependent manner, extending its cell-surface signaling role beyond neurons and tumor cells.","evidence":"Anti-OBCAM IgG vs Fab comparison, overexpression, Ki-67, and in vivo brain injury model","pmids":["19943852"],"confidence":"Medium","gaps":["Signaling pathway downstream of clustering not defined","Single-lab phenotype"]},{"year":2012,"claim":"The core molecular mechanism of tumor suppression was defined: OPCML acts as a cell-surface repressor-adaptor binding extracellular domains of specific RTKs and routing them through non-clathrin/caveolin-1 endocytosis to proteasomal degradation.","evidence":"Co-IP, clathrin vs non-clathrin trafficking assays, ubiquitination and proteasome inhibition, and recombinant domain 1-3 rescue in vitro and in vivo","pmids":["22585860"],"confidence":"High","gaps":["How specificity for this RTK repertoire is encoded not resolved","Adaptor proteins linking OPCML to the endocytic machinery unidentified"]},{"year":2015,"claim":"Restored OPCML was shown to inhibit TGFβ-Smad signaling and reverse partial EMT in colorectal cancer, generalizing its tumor-suppressor reach beyond ovarian tissue and beyond RTK degradation.","evidence":"Ectopic expression, Smad phosphorylation blotting, EMT marker and invasion assays, nuclear receptor association","pmids":["26175934"],"confidence":"Medium","gaps":["Mechanism connecting a GPI-anchored protein to Smad signaling unclear","Functional role of ERRα/RORα association untested"]},{"year":2017,"claim":"OPCML was shown to bind HER2 but not EGFR and to disrupt HER2-EGFR heterodimers, providing a distinct mechanism (heterodimer disruption) that sensitizes cells to EGFR/HER2 inhibitors.","evidence":"Co-IP, heterodimerization assay, and lapatinib/erlotinib viability assays with clinical correlation","pmids":["28775148"],"confidence":"Medium","gaps":["Reciprocal validation of heterodimer disruption limited","Generalizability across HER2-driven tumors not tested"]},{"year":2018,"claim":"A phosphatase-coupling mechanism was established: OPCML preferentially binds ligand-activated AXL, concentrates it in cholesterol-rich domains, and juxtaposes it with PTPRG for dephosphorylation, blocking AXL-driven cMET/EGFR transactivation and EMT.","evidence":"Reciprocal Co-IP, lipid domain fractionation, PTPRG proximity/activity assays, ERK and migration/invasion assays, and in vivo AXL-inhibitor combination","pmids":["29907679"],"confidence":"High","gaps":["Whether the PTPRG-coupling mode applies to the other RTK targets unknown","Direct ternary complex structure not resolved"]},{"year":2019,"claim":"The OPCML crystal structure and structure-guided mutagenesis defined its three-Ig-domain architecture, membrane-distal homodimerization, and showed that clinical missense variants abolish RTK binding and tumor-suppressor activity, mechanistically linking structure to function.","evidence":"X-ray crystallography at 2.65 Å with mutagenesis, anchorage-independent growth, Co-IP, migration/invasion, and in vivo tumor assays","pmids":["31316070"],"confidence":"High","gaps":["Co-crystal with an RTK partner not obtained","Functional role of the homodimer interface in vivo not dissected"]},{"year":2019,"claim":"Genetic knockout connected OPCML to a defined synaptic signaling axis, showing it interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation, with pharmacological rescue.","evidence":"Co-IP, Opcml knockout mice, phospho-cofilin blotting, F-actin and spine analyses, behavior, and aripiprazole rescue","pmids":["31577955"],"confidence":"High","gaps":["How EphB2 binding couples to cofilin not mechanistically resolved","Relationship to its RTK-degradation role in tumors unexplored"]},{"year":2021,"claim":"In cholangiocarcinoma, restored OPCML was shown to act through AXL/STAT3 inactivation and Rho GTPase downregulation, reinforcing AXL as a recurrent target across tumor types.","evidence":"Ectopic expression with AXL/STAT3 blotting, Rho GTPase activity, and proliferation/migration/invasion assays","pmids":["34697068"],"confidence":"Medium","gaps":["Direct OPCML-AXL binding not re-demonstrated in this context","Link from AXL to Rho GTPases not mechanistically dissected"]},{"year":2022,"claim":"A transcriptional regulator of OPCML was identified, showing that GPBAR1 activation drives nuclear RAD21 to upregulate Opcml transcription and protect neurites in a Parkinson's model, placing OPCML downstream of a defined signaling-to-transcription axis.","evidence":"DA-neuron Gpbar1 knockdown, INT-777 activation, RAD21 nuclear fractionation, and synapse morphometry in mice","pmids":["36152741"],"confidence":"Medium","gaps":["Direct RAD21 binding to the Opcml promoter not shown","Whether this regulatory axis operates in non-dopaminergic tissues unknown"]},{"year":2024,"claim":"Electrophysiology in knockout mice defined the functional synaptic consequence of OPCML loss as impaired glutamatergic transmission via postsynaptic AMPA/NMDA receptor dysfunction with disrupted E/I balance.","evidence":"Whole-cell patch clamp, AMPAR/NMDAR current analysis, and aripiprazole rescue in Opcml knockout mice","pmids":["39420375"],"confidence":"Medium","gaps":["Molecular link between OPCML and receptor function not defined here","Single-lab electrophysiology"]},{"year":2025,"claim":"Proximity labeling identified OPCML as a direct binder of the AMPAR extracellular N-terminal domain during LTP, offering a candidate molecular basis for its control of glutamatergic transmission.","evidence":"Surface-restricted APEX2 proximity labeling, BioSITe proteomics, and direct OBCAM-AMPAR NTD binding assay (preprint)","pmids":["bio_10.1101_2025.07.11.664166"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Functional consequence of the NTD interaction on receptor trafficking not established"]},{"year":null,"claim":"How OPCML achieves target specificity — selecting particular RTKs and AMPARs, and choosing between degradation, phosphatase-coupling, and heterodimer-disruption outcomes — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No co-structure of OPCML with any RTK or AMPAR partner","Adaptors linking OPCML to endocytic/degradation machinery unidentified","Unifying principle across its tumor and neuronal roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,2,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,5,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,13,3,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,7,16]}],"complexes":[],"partners":["AXL","PTPRG","HER2","EPHA2","FGFR1","EPHB2","GRIA1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14982","full_name":"Opioid-binding protein/cell adhesion molecule","aliases":["IgLON family member 1"],"length_aa":345,"mass_kda":38.0,"function":"Binds opioids in the presence of acidic lipids; probably involved in cell contact","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14982/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OPCML","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OPCML","total_profiled":1310},"omim":[{"mim_id":"615053","title":"ANKYRIN REPEAT- AND SOCS BOX-CONTAINING PROTEIN 8; ASB8","url":"https://www.omim.org/entry/615053"},{"mim_id":"607938","title":"NEUROTRIMIN; NTM","url":"https://www.omim.org/entry/607938"},{"mim_id":"602005","title":"SORTILIN-RELATED RECEPTOR; SORL1","url":"https://www.omim.org/entry/602005"},{"mim_id":"600632","title":"OPIOID-BINDING PROTEIN/CELL ADHESION MOLECULE-LIKE; OPCML","url":"https://www.omim.org/entry/600632"},{"mim_id":"167000","title":"OVARIAN CANCER","url":"https://www.omim.org/entry/167000"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":35.4},{"tissue":"parathyroid gland","ntpm":9.7},{"tissue":"retina","ntpm":10.5}],"url":"https://www.proteinatlas.org/search/OPCML"},"hgnc":{"alias_symbol":["OPCM","OBCAM","IGLON1"],"prev_symbol":[]},"alphafold":{"accession":"Q14982","domains":[{"cath_id":"2.60.40.10","chopping":"44-133","consensus_level":"high","plddt":93.422,"start":44,"end":133},{"cath_id":"2.60.40.10","chopping":"142-222","consensus_level":"high","plddt":93.3557,"start":142,"end":222},{"cath_id":"2.60.40.10","chopping":"230-314","consensus_level":"high","plddt":94.1859,"start":230,"end":314}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14982","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14982-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14982-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OPCML","jax_strain_url":"https://www.jax.org/strain/search?query=OPCML"},"sequence":{"accession":"Q14982","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14982.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14982/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14982"}},"corpus_meta":[{"pmid":"12819783","id":"PMC_12819783","title":"OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12819783","citation_count":154,"is_preprint":false},{"pmid":"18714356","id":"PMC_18714356","title":"OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.","date":"2008","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/18714356","citation_count":96,"is_preprint":false},{"pmid":"12617969","id":"PMC_12617969","title":"Biochemical and ultrastructural analyses of IgLON cell adhesion molecules, Kilon and OBCAM in the rat brain.","date":"2003","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12617969","citation_count":63,"is_preprint":false},{"pmid":"17239010","id":"PMC_17239010","title":"Expression of cellular adhesion molecule 'OPCML' is down-regulated in gliomas and other brain tumours.","date":"2007","source":"Neuropathology 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a somatic missense mutation showed loss of function, and restored expression suppressed tumor growth in vitro and in vivo, establishing tumor suppressor function.\",\n      \"method\": \"Loss of heterozygosity analysis, methylation-specific PCR, ectopic expression with in vitro and in vivo tumor growth assays, somatic missense mutation functional analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (LOH, methylation, functional rescue in vitro and in vivo, mutation analysis) in a single rigorous study, widely replicated across subsequent labs\",\n      \"pmids\": [\"12819783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OBCAM (OPCML) is localized postsynaptically at dendritic and somatic synapses in adult cerebral cortex and hippocampus, and interacts both heterophilically and homophilically with the related IgLON family member Kilon, as demonstrated by cross-linker binding analysis and immunoprecipitation.\",\n      \"method\": \"Electron microscopy, immunohistochemistry, cross-linker binding analysis, immunoprecipitation\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by EM and reciprocal IP for interaction, single lab but two orthogonal methods\",\n      \"pmids\": [\"12617969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"OPCML functions as a cell-surface repressor-adaptor that negatively regulates a specific repertoire of receptor tyrosine kinases (EPHA2, FGFR1, FGFR3, HER2, HER4) in ovarian cancer by binding their extracellular domains, redirecting trafficking via non-clathrin/caveolin-1-associated endocytosis, and promoting polyubiquitination-dependent proteasomal degradation. Recombinant OPCML domains 1–3 recapitulate this mechanism in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, trafficking assays (clathrin vs. non-clathrin endocytosis), ubiquitination assays, proteasome inhibitor experiments, in vitro and in vivo (murine intraperitoneal) tumor growth assays with recombinant protein\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, trafficking, ubiquitination, proteasome inhibition, in vivo rescue) in a single rigorous study establishing the mechanistic pathway\",\n      \"pmids\": [\"22585860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OBCAM (OPCML) is localized at postsynaptic spines in hippocampal neurons; inhibition of OBCAM function with specific antibody significantly decreased synapse number on dendrites, antisense knockdown impaired synapse formation, and overexpression augmented synapse formation, establishing a role in synaptogenesis. Activity-dependent internalization of OBCAM occurs via a lipid raft/cholesterol-dependent (filipin-sensitive) pathway.\",\n      \"method\": \"Immunofluorescence microscopy, antibody function-blocking, antisense oligodeoxynucleotide knockdown, plasmid overexpression, 4-aminopyridine neuronal activity stimulation, filipin treatment internalization assay\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal loss-of-function and gain-of-function approaches with quantitative phenotypic readout, single lab but rigorous\",\n      \"pmids\": [\"17658490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Oncogenic RAS (HRASV12) directly mediates epigenetic silencing of OPCML by promoting CpG island promoter hypermethylation; siRNA knockdown of HRASV12 reversed OPCML promoter methylation and restored expression, demonstrating that elevated RAS signaling drives OPCML epigenetic inactivation.\",\n      \"method\": \"Methylation-sensitive PCR, 5-aza-2'-deoxycytidine demethylation, stable siRNA knockdown of HRASV12, RT-PCR for OPCML re-expression\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (siRNA rescue) plus pharmacological demethylation and methylation-sensitive PCR; single lab but multiple orthogonal approaches clearly establishing causal direction\",\n      \"pmids\": [\"16384911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"OPCML directly interacts with the activated RTK AXL (preferentially when AXL is bound by its ligand Gas6), causing AXL to accumulate in cholesterol-rich lipid domains where OPCML resides. There, OPCML brings phospho-AXL into proximity with the lipid domain-restricted phosphatase PTPRG, which dephosphorylates AXL, preventing AXL-mediated transactivation of cMET and EGFR, inhibiting sustained phospho-ERK signaling, Slug induction, EMT, cell migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, lipid domain fractionation, phosphatase (PTPRG) proximity/activity assays, ERK signaling assays, migration/invasion assays, in vivo AXL inhibitor (R428) combination experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, lipid domain fractionation, multiple downstream signaling readouts, in vivo validation; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"29907679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"X-ray crystal structure of OPCML solved to 2.65 Å resolution reveals an extended arrangement of three immunoglobulin-like domains and homodimerization via contacts between membrane-distal domains. Somatic missense mutations from tumor databases were shown to impair anchorage-independent growth, interaction with activated RTKs, migration, invasion in vitro, and tumor growth in vivo.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis of clinical missense variants, anchorage-independent growth assays, Co-IP with RTKs, migration/invasion assays, in vivo tumor growth assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and multiple in vitro/in vivo assays in a single rigorous study\",\n      \"pmids\": [\"31316070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"OPCML interacts with EphB2 in hippocampal neurons and controls spine stability by regulating the ephrin-EphB2-cofilin signaling pathway. Opcml ablation in mice reduces phosphorylated cofilin levels and dysregulates F-actin dynamics, disturbing spine maturation; aripiprazole partially restores behavior and phospho-cofilin levels.\",\n      \"method\": \"Co-immunoprecipitation (OPCML-EphB2 interaction), Opcml knockout mouse model, phospho-cofilin immunoblotting, F-actin dynamics assays, spine morphology analysis, behavioral testing (cognitive, sensorimotor gating), pharmacological rescue with aripiprazole\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing direct interaction, genetic knockout with defined molecular phenotype (phospho-cofilin, F-actin), pharmacological rescue; multiple orthogonal methods\",\n      \"pmids\": [\"31577955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OPCML interacts with HER2 but not EGFR; this interaction disrupts HER2-EGFR heterodimer formation and sensitizes HER2-expressing ovarian and breast cancer cells to the EGFR/HER2 inhibitors lapatinib and erlotinib, demonstrating that OPCML-HER2 binding indirectly suppresses EGFR signaling through heterodimer disruption.\",\n      \"method\": \"Co-immunoprecipitation (OPCML-HER2 interaction), HER2-EGFR heterodimerization assay, cell viability assays with lapatinib/erlotinib, in vitro and clinical correlation\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional drug sensitization assays, single lab, two orthogonal in vitro methods\",\n      \"pmids\": [\"28775148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Restored OPCML expression in colorectal cancer cells inhibits TGFβ-Smad signaling, reverses a partial epithelial-to-mesenchymal transition (EMT), and inhibits cell migration and invasion; OPCML expression was also found to be associated with the nuclear receptors ERRα and RORα.\",\n      \"method\": \"Ectopic OPCML expression, Smad phosphorylation western blotting, EMT marker analysis, migration/invasion assays, nuclear receptor association assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ectopic expression with defined signaling readouts (Smad phosphorylation, EMT markers), single lab with multiple assays\",\n      \"pmids\": [\"26175934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"OBCAM (OPCML) is linked to the cell membrane via a glycosylphosphatidylinositol (GPI) anchor, demonstrated by release from the membrane upon treatment with phosphatidylinositol-specific phospholipase C (PI-PLC) in transfected cells and in bovine brain membranes.\",\n      \"method\": \"PI-PLC treatment of transfected Cos1 cells and bovine brain P2 membranes, immunoblotting, N-glycanase digestion showing N-glycosylation\",\n      \"journal\": \"Brain research. Molecular brain research / Neurochemistry international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct enzymatic cleavage (PI-PLC) demonstrating GPI anchor, replicated in both transfected cells and native brain membranes in independent studies\",\n      \"pmids\": [\"8965653\", \"8740443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"GP55 (a chick homolog closely related to OBCAM/OPCML) inhibits neurite outgrowth from dorsal root ganglion neurons when presented as a substrate, and an antiserum against it reverses this inhibition, establishing that the IgLON family members can function as inhibitors of neurite outgrowth.\",\n      \"method\": \"Substrate-bound neurite outgrowth inhibition assay, antibody reversal assay, peptide sequencing, PCR cloning with homology to OBCAM\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro functional assay with antibody reversal control; this is a chick ortholog study with functional relevance to the mammalian protein\",\n      \"pmids\": [\"9004047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OBCAM (OPCML) in astrocytes is expressed prominently at filopodia and cellular processes and controls astrocyte proliferation and cell size; antibody-induced clustering of OBCAM (but not Fab fragment treatment) promoted astrocyte proliferation, and OBCAM overexpression increased astrocyte cell size. OBCAM expression is upregulated on reactive astrocytes after brain injury in vivo.\",\n      \"method\": \"Confocal microscopy, anti-OBCAM IgG vs. Fab fragment treatment, OBCAM overexpression, Ki-67 proliferation marker, in vivo brain injury model\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Fab vs. whole IgG comparison provides mechanistic insight into clustering requirement; overexpression phenotype; single lab with multiple methods\",\n      \"pmids\": [\"19943852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"OBCAM (OPCML) is efficiently targeted to the dendritic surface of polarized cortical and hippocampal neurons, resides in lipid rafts (resistant to Triton X-100 extraction at 4°C and released by PI-PLC), and shows surface localization preferentially on dendrites compared to somata.\",\n      \"method\": \"Live-cell immunofluorescence (pre-fixation antibody labeling), PI-PLC treatment, detergent fractionation (Triton X-100 raft isolation), double labeling with synapsin I and MAP2\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell surface labeling with biochemical fractionation confirming raft localization; single lab, two orthogonal methods\",\n      \"pmids\": [\"12850579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ectopic OPCML expression in cholangiocarcinoma cells inhibits proliferation by inducing apoptosis via inactivation of AXL/STAT3 signaling, and suppresses migration and invasion by downregulating Rho GTPases (RHOA, RAC1, CDC42).\",\n      \"method\": \"Ectopic OPCML expression (pcDNA3.1 vector), AXL/STAT3 phosphorylation western blotting, Rho GTPase activity assays, proliferation, migration, and invasion assays\",\n      \"journal\": \"Cancer genomics & proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ectopic expression with defined signaling readouts and Rho GTPase measurements; single lab, multiple pathways examined\",\n      \"pmids\": [\"34697068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPBAR1 activation increases OPCML expression in dopaminergic neurons by promoting nuclear localization of the cohesin subunit RAD21, which in turn upregulates Opcml transcription, thereby protecting neurites and synapses in a Parkinson's disease model. This establishes RAD21 as a transcriptional regulator upstream of OPCML.\",\n      \"method\": \"DA neuron-specific Gpbar1 knockdown in mice, central GPBAR1 activation with INT-777, RAD21 nuclear fractionation/localization, OPCML expression measurement, neurite/synapse morphometry, behavioral assays\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic knockdown and pharmacological activation with mechanistic fractionation data, single lab\",\n      \"pmids\": [\"36152741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Opcml deficiency in mice leads to decreased neuronal excitability and impaired glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons, specifically via postsynaptic AMPA/NMDA receptor dysfunction, resulting in disturbed excitatory/inhibitory balance. Aripiprazole rescued impaired glutamatergic transmission alongside behavioral improvement.\",\n      \"method\": \"Whole-cell patch clamp recordings in Opcml knockout mice, AMPAR/NMDAR current analysis, E/I balance measurements, pharmacological rescue with aripiprazole\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct electrophysiology in genetic knockout model with pharmacological rescue, single lab\",\n      \"pmids\": [\"39420375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Lentiviral expression of OPCML in ovarian cancer cell line A2780 increased cell-surface adhesion in all tested cell lines, arrested A2780 cells in G0/G1, reduced proliferation, and markedly suppressed tumorigenicity in nude mice, while having no effect on the OCC1 or normal CD1 mouse ovarian surface epithelial cells.\",\n      \"method\": \"Lentiviral OPCML transduction, cell aggregation assay, flow cytometry cell cycle analysis, CCK-8/proliferation assay, nude mouse xenograft tumorigenicity assay\",\n      \"journal\": \"Zhonghua fu chan ke za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional assays with near-100% infection efficiency; single lab, multiple assays\",\n      \"pmids\": [\"16762191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OBCAM (OPCML) directly interacts with the extracellular N-terminal domain (NTD) of AMPA-type glutamate receptors (AMPARs), as identified by surface-restricted APEX2 proximity labeling during chemical LTP induction in cultured neurons; OBCAM was among four IgLON family members enriched in the AMPAR extracellular interactome after cLTP.\",\n      \"method\": \"Surface-restricted APEX2 proximity labeling, BioSITe-based proteomics, direct binding assay between OBCAM and AMPAR NTD\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — surface-restricted proximity labeling and direct NTD interaction assay; preprint, single lab, two orthogonal methods\",\n      \"pmids\": [\"bio_10.1101_2025.07.11.664166\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"OPCML (OBCAM) is a GPI-anchored, lipid raft-resident IgLON family cell adhesion molecule that functions as a broad tumor suppressor by binding the extracellular domains of specific receptor tyrosine kinases (including EPHA2, FGFR1, FGFR3, HER2, HER4, and AXL), redirecting them to non-clathrin/caveolin-1 endosomal pathways for polyubiquitination and proteasomal degradation, and cooperating with the phosphatase PTPRG to dephosphorylate and inactivate AXL; in neurons, it localizes postsynaptically at dendritic spines, interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation, and directly binds AMPA receptor extracellular domains to modulate synaptic plasticity, while its expression is epigenetically silenced in diverse cancers through RAS-driven CpG island promoter hypermethylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OPCML (OBCAM) is a GPI-anchored, lipid raft-resident IgLON family cell-surface adhesion molecule that acts as a broad tumor suppressor and a regulator of synaptic structure [#0, #10, #2]. Its three-immunoglobulin-like-domain ectodomain adopts an extended arrangement and homodimerizes through membrane-distal contacts; clinical missense variants mapped onto this structure impair RTK binding, anchorage-independent growth, migration, invasion, and tumor growth [#6]. As a cell-surface repressor-adaptor, OPCML binds the extracellular domains of a defined repertoire of receptor tyrosine kinases (EPHA2, FGFR1, FGFR3, HER2, HER4), redirecting them through non-clathrin/caveolin-1 endocytosis toward polyubiquitination-dependent proteasomal degradation [#2]. It additionally captures ligand-activated AXL into cholesterol-rich domains where it juxtaposes phospho-AXL with the lipid-domain phosphatase PTPRG, driving AXL dephosphorylation and blocking downstream ERK signaling, EMT, migration, and invasion [#5], and its binding to HER2 disrupts HER2-EGFR heterodimers to suppress EGFR signaling [#8]. OPCML expression is epigenetically silenced in cancer by oncogenic RAS-driven CpG island promoter hypermethylation [#0, #4]. In the nervous system, OPCML localizes to postsynaptic dendritic spines within lipid rafts and undergoes activity-dependent, cholesterol-dependent internalization to promote synaptogenesis [#3, #13]; it interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation [#7] and shapes glutamatergic transmission through postsynaptic AMPA/NMDA receptor function [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing how OPCML attaches to the cell surface defined it as a GPI-anchored, glycosylated membrane protein rather than a transmembrane receptor, framing all later interpretations of its raft residence and adaptor function.\",\n      \"evidence\": \"PI-PLC release and N-glycanase digestion in transfected cells and native bovine brain membranes\",\n      \"pmids\": [\"8965653\", \"8740443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address signaling output or binding partners\", \"No structural detail of the ectodomain\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"A closely related IgLON ortholog (GP55) was shown to inhibit neurite outgrowth and to be reversible by antibody, providing the first functional readout that IgLON family members act as cell-surface modulators of neuronal growth.\",\n      \"evidence\": \"Substrate-bound neurite outgrowth inhibition with antibody reversal in DRG neurons (chick ortholog)\",\n      \"pmids\": [\"9004047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chick ortholog, not direct OPCML evidence\", \"Molecular partner mediating inhibition not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"OPCML was established as a tumor suppressor in epithelial ovarian cancer, answering whether its frequent loss is causal by combining allele loss, methylation, a loss-of-function mutation, and functional rescue.\",\n      \"evidence\": \"LOH, methylation-specific PCR, somatic mutation analysis, and ectopic expression with in vitro and in vivo tumor growth assays\",\n      \"pmids\": [\"12819783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of suppression unresolved at this stage\", \"Binding partners not yet identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Parallel neuronal work showed OPCML resides postsynaptically in dendritic lipid rafts and engages other IgLONs, indicating a synaptic adhesion role distinct from its tumor context.\",\n      \"evidence\": \"EM/immunohistochemistry, cross-linker binding and IP with Kilon, live-cell surface labeling and detergent raft fractionation\",\n      \"pmids\": [\"12617969\", \"12850579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of synaptic localization not yet tested\", \"Homophilic vs heterophilic binding stoichiometry unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Lentiviral restoration of OPCML demonstrated cell-cycle arrest, increased surface adhesion, and suppressed tumorigenicity, refining the tumor-suppressor phenotype to specific cellular outputs.\",\n      \"evidence\": \"Lentiviral transduction, aggregation assay, flow cytometry, proliferation and xenograft assays in ovarian cancer cells\",\n      \"pmids\": [\"16762191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking adhesion to cell-cycle arrest not defined\", \"Effect restricted to a subset of lines\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The cause of OPCML silencing was traced to oncogenic RAS, showing that elevated RAS signaling drives CpG island promoter hypermethylation and that this is reversible.\",\n      \"evidence\": \"Methylation-sensitive PCR, 5-aza demethylation, and HRASV12 siRNA rescue restoring expression\",\n      \"pmids\": [\"16384911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate methyltransferase machinery not identified\", \"Whether other oncogenes converge on the same promoter unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Loss- and gain-of-function in hippocampal neurons established OPCML as a positive regulator of synaptogenesis and revealed activity-dependent, cholesterol-dependent internalization, linking its raft residence to a dynamic trafficking cycle.\",\n      \"evidence\": \"Antibody blocking, antisense knockdown, overexpression, activity stimulation, and filipin internalization assay\",\n      \"pmids\": [\"17658490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of synaptogenesis not defined here\", \"Receptor partner mediating the effect unknown at this stage\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"OPCML was shown to control astrocyte proliferation and size in a clustering-dependent manner, extending its cell-surface signaling role beyond neurons and tumor cells.\",\n      \"evidence\": \"Anti-OBCAM IgG vs Fab comparison, overexpression, Ki-67, and in vivo brain injury model\",\n      \"pmids\": [\"19943852\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway downstream of clustering not defined\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The core molecular mechanism of tumor suppression was defined: OPCML acts as a cell-surface repressor-adaptor binding extracellular domains of specific RTKs and routing them through non-clathrin/caveolin-1 endocytosis to proteasomal degradation.\",\n      \"evidence\": \"Co-IP, clathrin vs non-clathrin trafficking assays, ubiquitination and proteasome inhibition, and recombinant domain 1-3 rescue in vitro and in vivo\",\n      \"pmids\": [\"22585860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specificity for this RTK repertoire is encoded not resolved\", \"Adaptor proteins linking OPCML to the endocytic machinery unidentified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Restored OPCML was shown to inhibit TGFβ-Smad signaling and reverse partial EMT in colorectal cancer, generalizing its tumor-suppressor reach beyond ovarian tissue and beyond RTK degradation.\",\n      \"evidence\": \"Ectopic expression, Smad phosphorylation blotting, EMT marker and invasion assays, nuclear receptor association\",\n      \"pmids\": [\"26175934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting a GPI-anchored protein to Smad signaling unclear\", \"Functional role of ERRα/RORα association untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"OPCML was shown to bind HER2 but not EGFR and to disrupt HER2-EGFR heterodimers, providing a distinct mechanism (heterodimer disruption) that sensitizes cells to EGFR/HER2 inhibitors.\",\n      \"evidence\": \"Co-IP, heterodimerization assay, and lapatinib/erlotinib viability assays with clinical correlation\",\n      \"pmids\": [\"28775148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of heterodimer disruption limited\", \"Generalizability across HER2-driven tumors not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A phosphatase-coupling mechanism was established: OPCML preferentially binds ligand-activated AXL, concentrates it in cholesterol-rich domains, and juxtaposes it with PTPRG for dephosphorylation, blocking AXL-driven cMET/EGFR transactivation and EMT.\",\n      \"evidence\": \"Reciprocal Co-IP, lipid domain fractionation, PTPRG proximity/activity assays, ERK and migration/invasion assays, and in vivo AXL-inhibitor combination\",\n      \"pmids\": [\"29907679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the PTPRG-coupling mode applies to the other RTK targets unknown\", \"Direct ternary complex structure not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The OPCML crystal structure and structure-guided mutagenesis defined its three-Ig-domain architecture, membrane-distal homodimerization, and showed that clinical missense variants abolish RTK binding and tumor-suppressor activity, mechanistically linking structure to function.\",\n      \"evidence\": \"X-ray crystallography at 2.65 Å with mutagenesis, anchorage-independent growth, Co-IP, migration/invasion, and in vivo tumor assays\",\n      \"pmids\": [\"31316070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-crystal with an RTK partner not obtained\", \"Functional role of the homodimer interface in vivo not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetic knockout connected OPCML to a defined synaptic signaling axis, showing it interacts with EphB2 to regulate cofilin phosphorylation and F-actin dynamics for spine maturation, with pharmacological rescue.\",\n      \"evidence\": \"Co-IP, Opcml knockout mice, phospho-cofilin blotting, F-actin and spine analyses, behavior, and aripiprazole rescue\",\n      \"pmids\": [\"31577955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EphB2 binding couples to cofilin not mechanistically resolved\", \"Relationship to its RTK-degradation role in tumors unexplored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"In cholangiocarcinoma, restored OPCML was shown to act through AXL/STAT3 inactivation and Rho GTPase downregulation, reinforcing AXL as a recurrent target across tumor types.\",\n      \"evidence\": \"Ectopic expression with AXL/STAT3 blotting, Rho GTPase activity, and proliferation/migration/invasion assays\",\n      \"pmids\": [\"34697068\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct OPCML-AXL binding not re-demonstrated in this context\", \"Link from AXL to Rho GTPases not mechanistically dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A transcriptional regulator of OPCML was identified, showing that GPBAR1 activation drives nuclear RAD21 to upregulate Opcml transcription and protect neurites in a Parkinson's model, placing OPCML downstream of a defined signaling-to-transcription axis.\",\n      \"evidence\": \"DA-neuron Gpbar1 knockdown, INT-777 activation, RAD21 nuclear fractionation, and synapse morphometry in mice\",\n      \"pmids\": [\"36152741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAD21 binding to the Opcml promoter not shown\", \"Whether this regulatory axis operates in non-dopaminergic tissues unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Electrophysiology in knockout mice defined the functional synaptic consequence of OPCML loss as impaired glutamatergic transmission via postsynaptic AMPA/NMDA receptor dysfunction with disrupted E/I balance.\",\n      \"evidence\": \"Whole-cell patch clamp, AMPAR/NMDAR current analysis, and aripiprazole rescue in Opcml knockout mice\",\n      \"pmids\": [\"39420375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between OPCML and receptor function not defined here\", \"Single-lab electrophysiology\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proximity labeling identified OPCML as a direct binder of the AMPAR extracellular N-terminal domain during LTP, offering a candidate molecular basis for its control of glutamatergic transmission.\",\n      \"evidence\": \"Surface-restricted APEX2 proximity labeling, BioSITe proteomics, and direct OBCAM-AMPAR NTD binding assay (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.07.11.664166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Functional consequence of the NTD interaction on receptor trafficking not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OPCML achieves target specificity — selecting particular RTKs and AMPARs, and choosing between degradation, phosphatase-coupling, and heterodimer-disruption outcomes — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-structure of OPCML with any RTK or AMPAR partner\", \"Adaptors linking OPCML to endocytic/degradation machinery unidentified\", \"Unifying principle across its tumor and neuronal roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 2, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 13, 3, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 7, 16]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AXL\", \"PTPRG\", \"HER2\", \"EPHA2\", \"FGFR1\", \"EphB2\", \"GRIA1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}